The present invention relates to a process for preparing quinolonecarboxylic acids, particularly to a process for preparing quinolonecarboxylic acids from acetylbenzene polyhalides.
People have increasingly paid attention to anti-infection drugs of quinolones due to their excellent properties. Quinolonecarboxylic acids are key intermediates of the anti-infection drugs since all the drugs of quinolones are based on such intermediates followed by a series of reactions. Therefore, the synthesis of the intermediates of quinolonecarboxylic acids is very important in the preparation of the quinolone drugs.
Various methods of preparing quinolonecarboxylic acids have been disclosed in the prior art. For example, Gaticarboxylic acid is prepared starting from 2,4,5-trifluoro-3-methoxylbenzene carboxylic acid, and Sparcarboxylic acid is prepared starting from pentafluorobenzenecarboxylic acid. However, the yield of the subject compound in these methods is not satisfied. The invention is hereby provided to overcome the drawbacks.
One object of the invention is to provide a new process for preparing quinolonecarboxylic acid derivatives starting from acetylbenzene polyhalides. The process according to the invention has fewer steps but a higher yield to obtain the subject compound.
According to the present invention, the process for preparing quinolonecarboxylic acid derivatives having the formula (I): 
wherein R1 is H, halogen, or amino,
R2 is halogen,
R3 is H, halogen, C1-4alkoxyl, or CN,
R4 is selected from the group consisting of C3-6cycloalkyl, C1-4alkyl, C1-4alkoxylC1-4alkyl, and C1-4alkylaminoC1-4alkyl,
comprising the steps of:
i) reacting a compound of the formula (II) 
xe2x80x83wherein R1, R2 and R3 are defined as above, and R7 is a halogen, with an alkyl carbonate to obtain a compound of the formula (III), 
xe2x80x83wherein R8 is methyl or ethyl;
ii) reacting a compound of the formula (III) successively with an alkyl orthoformate and a compound of the formula (IV) R4NH2 to obtain a compound of the formula (V), 
iii) cyclizing the compound of the formula (V) in the presence of a base to form a compound of the formula (VI); and 
iv) hydrolyzing the compound of the formula (VI) to obtain a compound of the formula (I).
The another object of the invention is to provide some compounds having the formula (II), 
In the formula (II), those compounds, in which R1 is H, or Cl; R2 is Cl; R3 is F, C1-4 alkoxy, or CN; and R7 is Cl, are novel compounds.
In the process for preparing compounds of the formula (I) according to the present invention, R1 is preferably H, F, or NH2; R2 is preferably F or Cl; R3 is preferably F, CN or CH3; and R4 is preferably cyclopropyl or cyclohexyl.
Methyl carbonate or ethyl carbonate can be used in the reaction with compounds having the formula (II). This reaction in general is carried out in the presence of a base in organic solvents. Preferably, carbonates themselves are used as reaction solvents. The base used herein may be NaH or sodium alkoxide.
In general, the reaction between compounds of the formula (III) and orthoformates may be carried out in the presence of diacetyl oxide, and the resultant may be directly reacted with R4NH2 of the formula (IV) to obtain a compound having the formula (V).
Cyclization of the compound of the formula (V) can be carried out in an organic solvent in the presence of a base to obtain a compound having the formula (VI). Preferable solvent is DMF, and anhydrous sodium carbonate may be selected as the base.
The compound of the formula (VI) can be hydrolyzed to give the corresponding compound of the formula (I) using a conventional method in the art.
In the process of the present invention, the compound of the formula (I) in which R1 is NH2 can be converted from a compound thereof in which R1 is halogen. The reaction scheme is shown as follows: 
In the compound of the formula (II), R1 is preferably H, and R3 is preferably F, OCH3 or CN.
Although the compound having the formula (II) can be prepared by many methods in the art, it is prepared in the invention starting from benzene polyhalides that can be easily obtained commercially.
The invention will be further illustrated with the following examples.
Preparation of Quinolonecarboxylic Acids